Polymorphism can be defined as the ability of the same chemical substance to exist in different crystalline structures. The different structures are are referred to as polymorphs, polymorphic modification or form.
It has been known that 17-β-N-ter. butyl carbamoyl)-4-aza-5-α-androst-1-en-3-one exists in two polymorphic forms i.e., Form-I and Form-II which are patented by Merck & Co. Inc. (U.S. Pat. Nos. 5,652,365 and 5,886,184)
The polymorphic form-I is characterized by a differential scanning calorimetry (DSC) curve, at heating rate of 20° C./min and in a closed cup, exhibiting a minor endotherm with a peak temperature of about 232° C.; an extrapolated onset temperature of about 223° C. with an associated heat of about 11 joules/gm and by a major melting endotherm with a peak temperature of about of 261° C.; an extrapolated onset temperature of about 258° C. with an associated heat of about 89 J/gm. The X-ray powder diffraction pattern is characterized by d-spacings of 6.44, 5.69, 5.36, 4.89, 4.55, 4.31, 3.85, 3.59 and 3.14. The FT-IR spectrum (in KBr) shows bands at 3431, 3237, 1692, 1666, 1602 and 688 cm−1.
The polymorphic form-II is characterized by a differential scanning calorimetry (DSC) curve, at heating rate of 20° C./min and in a closed cup, exhibiting a single melting endotherm with a peak temperature of about 261° C.; an extrapolated onset temperature of about 258° C., with an associated heat of about 89 J/g. The X-ray powder diffraction pattern is characterized by d-spacings of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25. The FT-IR spectrum (in KBr) shows bands at 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm−1.
Two polymorphic forms and two pseudopolymorphic forms have been characterized using single crystal X-ray diffraction studies by Irena Wawrzycka et al and the results are published in the Journal of Molecular Structure, 474 (1999) 157-166.
The two polymorphic forms referred as 1 and 2 are same as the Form-I and Form-II mentioned above.
The pseudopolymorphic form 1a crystallizes in Monoclinic space group P21 with cell dimensions a=12.120(1), b=8.1652(7), c=13.577(1)A°, β=111.530° containing two molecules in unit cell. The lattice contains one molecule of acetic acid. It decomposes losing acetic acid and recrystallizes in the range 170-174° C. having melting point 255-257° C.
The pseudopolymorphic form 1b crystallizes in orthorhombic space group P212121 having cell dimensions a=8.173 (3), b=18.364 (6), c=35.65 (2) containing four molecules in unit cell. The lattice contains one molecule of ethyl acetate for two molecules of Finasteride. The melting point of form 1b is reported as 252-255° C.
While doing process development to optimize the yield and quality of 17-β-(N-ter. butyl carbamoyl)-4-aza-5-α-androst-1-en-3-one, different crystallization and isolation methods were used with different combinations of organic solvents and by varying the various parameters like temperature and volume etc.
All samples which were isolated in different methods were submitted for regular analysis and subjected to polymorphic characterizations studies. From this we found that 17-β-(N-ter. butyl carbamoyl)-4-aza-5-α-androst-1-en-3-one exists in additional polymorphic/pseudopolymorphic forms namely Form-III, Form-IV, and Form-V which are different from Form-I and Form-II disclosed in the prior art.
The XRD data and thermal characteristics of the pseudopolymorphic forms Form-IV and Form-V reasonably match with those of the pseudopolymorphs 1b and 1a mentioned above respectively.